GOLD in Action: Foiling a Protein–Protein Interaction to Help Fight Cancer
Drug Repurposing Using GOLD: the Search for a New Non-Covalent Inhibitor
Here we highlight a work by Xia Zhang, Qingxiang Sun, and co-workers, where the team used the protein docking software GOLD and CHEMPLP-based ranking to identify an approved drug as an inhibitor of a key protein–protein interaction (PPI) in the fight against cancer.
The full article can be accessed here – J. Med. Chem. 2023, 66, 2, 1574–1582.
The Target: CRM1
Chromosome region maintenance 1 (CRM1), also known as exportin 1 (XPO1), is a nuclear export protein that is overexpressed in many cancer types.
CRM1 is hence an attractive cancer drug target that has been the centre of several development programs.
Non-Covalent Inhibitors
Selinexor (KPT-330) is a covalent CRM1 inhibitor that was approved in 2019.
Despite being more difficult to develop, non-covalent inhibitors may offer better safety and efficacy profiles, along with increased resilience to resistance.
Drug Repurposing
In this work, the team used a drug repurposing approach to search for non-covalent inhibitors effective against CRM1.
Docking studies with GOLD led to the identification of zafirlukast as a non-covalent binder, which displayed in vitro activity against a broad range of cancer types.
A Drug Repurposing Approach Using GOLD
The study started with virtual screening of marketed drugs against CRM1 to identify potential lead scaffolds for this target.
The structures of the approved drugs were docked into the CRM1 active site and docking studies were performed using GOLD. Docked poses were scored using CCDC’s CHEMPLP, and the researchers ranked the poses by the CHEMPLP scores.
Based on the output of GOLD, zafirlukast (ZAF) was identified as a novel non-covalent and stable CRM1 inhibitor first using a nuclear-export-signal (NES) pull-down assay and then through further in vitro studies.
The researchers also observed resilience to the C528S mutation in ZAF, an obstacle to other ligands.
The Binding Mode of ZAF and Its Activity
To investigate the binding mode of ZAF, the team obtained a crystal structure of the latter complexed with CRM1. It was observed that ZAF closely matched the shape of the markedly flexible NES groove of CRM1, and that the observed interaction between ZAF and CRM1 was entirely hydrophobic, with no hydrogen bonds present.
These observations enabled the scientists to expand the study to other ZAF derivatives. In particular, molecular docking with GOLD suggested that the m-tolyl and p-tolyl ZAF derivatives were also compatible with the NES groove of CRM1.
Finally, ZAF displayed activity against a broad range of cancer types in vitro, inhibiting the growth of cancer cells, and synergy was observed when combined with the chemotherapy drug doxorubicin.
By using a drug repurposing approach, this work reveals key findings in the design of novel non-covalent CRM1 inhibitors for the fight against cancer.
